In peripartum cardiomyopathy plasminogen activator inhibitor-1 is a potential new biomarker with controversial roles

AIMS Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously healthy women. A common pathomechanism in PPCM involves the angiostatic 16kDa-prolactin (16kDa-PRL) fragment, which via NF-κB-mediated upregulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyze whether the plasminogen-activator-inhibitor-1 (PAI-1) is involved in PPCM pathophysiology. METHODS/RESULTS In healthy age-matched postpartum women (PP-Ctrl, n = 53, left-ventricular-ejection-fraction, LVEF>55%), PAI-1 plasma levels were within the normal range (21±10 ng/ml), but significantly elevated (64±38 ng/ml, p < 0.01) in postpartum PPCM patients at baseline (BL, n = 64, mean LVEF: 23±8%). At 6-months follow-up (FU, n = 23) PAI-1 levels decreased (36±14 ng/ml, p < 0.01 vs BL) and LVEF (49±11%) improved. Increased NT-proBNP and TroponinT did not correlate with PAI-1. C-reactive protein (CRP), interleukin (IL)-6 and IL-1β did not differ between PPCM patients and PP-Ctrl. MiR-146a) was 3.6-fold (p < 0.001) higher in BL-PPCM plasma compared with PP-Ctrl and correlated positively with PAI-1. In BL-PPCM serum, 16kDa-PRL coprecipitated with PAI-1, which was associated with higher (p < 0.05) uPAR-mediated NF-κB activation in endothelial cells compared with PP-Ctrl serum. Cardiac biopsies and dermal fibroblasts from PPCM patients displayed higher PAI-1 mRNA levels (p < 0.05) than healthy controls. In PPCM mice (due to a cardiomyocyte-specific-knockout for STAT3, CKO), cardiac PAI-1 expression was higher than in postpartum wildtype controls whereas a systemic PAI-1-knockout in CKO mice accelerated peripartum cardiac fibrosis, inflammation, heart failure, and mortality. CONCLUSION In PPCM patients, circulating and cardiac PAI-1 expression are upregulated. While circulating PAI-1 may add 16kDa-PRL to induce vascular impairment via the uPAR/NF-κB/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-κB-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised. TRANSLATIONAL PERSPECTIVE